tbuckley/cabot-search huggingface dataset:
Adagrasib in Advanced Solid Tumors Harboring a <i>KRAS</i><sup><i>G12C</i></sup> Mutation
Authors: Tanios S. Bekaii-Saab, Rona Yaeger, Alexander I. Spira, Meredith S. Pelster, Joshua K. Sabari, Navid Hafez, Minal Barve, Karen Velastegui, Xiaohong Yan, Aditya Shetty, Hirak Der-Torossian, Shubham Pant
Journal: Journal of Clinical Oncology (2023)

PURPOSE Adagrasib, a KRAS G12C inhibitor, has demonstrated clinical activity in patients with KRAS G12C -mutated non–small-cell lung cancer (NSCLC) and colorectal cancer (CRC). KRAS G12C mutations occur rarely in other solid tumor types. We report evaluation of the clinical activity and safety of adagrasib in patients with other solid tumors harboring a KRAS G12C mutation. METHODS In this phase II cohort of the KRYSTAL-1 study (ClinicalTrials.gov identifier: NCT03785249 ; phase Ib cohort), we evaluated adagrasib (600 mg orally twice daily) in patients with KRAS G12C -mutated advanced solid tumors (excluding NSCLC and CRC). The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival (PFS), overall survival, and safety. RESULTS As of October 1, 2022, 64 patients with KRAS G12C -mutated solid tumors were enrolled and 63 patients treated (median follow-up, 16.8 months). The median number of prior lines of systemic therapy was 2. Among 57 patients with measurable disease at baseline, objective responses were observed in 20 (35.1%) patients (all partial responses), including 7/21 (33.3%) responses in pancreatic and 5/12 (41.7%) in biliary tract cancers. The median duration of response was 5.3 months (95% CI, 2.8 to 7.3) and median PFS was 7.4 months (95% CI, 5.3 to 8.6). Treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of patients and grade 3-4 in 27.0%; there were no grade 5 TRAEs. TRAEs did not lead to treatment discontinuation in any patients. CONCLUSION Adagrasib demonstrates encouraging clinical activity and is well tolerated in this rare cohort of pretreated patients with KRAS G12C -mutated solid tumors.
Regeneration of Critical‐Sized Mandibular Defects Using 3D‐Printed Composite Scaffolds: A Quantitative Evaluation of New Bone Formation in In Vivo Studies
Authors: Sophia Dalfino, Paolo Savadori, Marco Piazzoni, Stephen Thaddeus Connelly, Aldo Bruno Giannì, Massimo Del Fabbro, Gianluca Martino Tartaglia, Lorenzo Moroni
Journal: Advanced Healthcare Materials (2023)

Mandibular tissue engineering aims to develop synthetic substitutes for the regeneration of critical size defects (CSD) caused by a variety of events, including tumor surgery and post-traumatic resections. Currently, the gold standard clinical treatment of mandibular resections (i.e., autologous fibular flap) has many drawbacks, driving research efforts toward scaffold design and fabrication by additive manufacturing (AM) techniques. Once implanted, the scaffold acts as a support for native tissue and facilitates processes that contribute to its regeneration, such as cells infiltration, matrix deposition and angiogenesis. However, to fulfil these functions, scaffolds must provide bioactivity by mimicking natural properties of the mandible in terms of structure, composition and mechanical behavior. This review aims to present the state of the art of scaffolds made with AM techniques that are specifically employed in mandibular tissue engineering applications. Biomaterials chemical composition and scaffold structural properties are deeply discussed, along with strategies to promote osteogenesis (i.e., delivery of biomolecules, incorporation of stem cells, and approaches to induce vascularization in the constructs). Finally, a comparison of in vivo studies is made by taking into consideration the amount of new bone formation (NB), the CSD dimensions, and the animal model.
Lariat preparation using a snare catheter for removal of a pancreaticogastric stent in a rendezvous stent exchange
Authors: Yoshihide Kanno, Haruka Okano, Fumisato Kozakai, Shinsuke Koshita, Takahisa Ogawa, Toshitaka Sakai, Kei Ito
Journal: Endoscopy (2023)

A 61-year-old man who had previously undergone pancreaticoduodenectomy underwent subsequent endoscopic ultrasound (EUS)-guided stent placement to bridge the jejunum, pancreatic duct, and stomach as treatment for pancreaticojejunal anastomosis stricture ([Fig. 1]). Stent exchange was attempted 6 months later ([Video 1]). However, a guidewire could not be advanced along or through the previous stent from the stomach due to an unstable scope position.
Comment on Duarte et al. Systematic Review and Network Meta-analysis of Neurostimulation for Painful Diabetic Neuropathy. Diabetes Care 2022;45:2466–2475
Authors: Ashwini D. Sharan, John A. Hatheway, Melissa Murphy, Tammy Dann, Michael A. Fishman, Xander Zuidema, Jan H.M. van Zundert, Maddie LaRue, Rachel Slangen
Journal: Diabetes Care (2023)
Wnt3a‐Loaded Hydroxyapatite Nanowire@Mesoporous Silica Core−Shell Nanocomposite Promotes the Regeneration of Dentin−Pulp Complex via Angiogenesis, Oxidative Stress Resistance, and Odontogenic Induction of Stem Cells
Authors: Nan Luo, Yu‐Wei Deng, Jin Wen, Xiao‐Chen Xu, Rui‐Xue Jiang, Jing‐Yu Zhan, Yu Zhang, Bing‐Qiang Lu, Feng Chen, Xi Chen
Journal: Advanced Healthcare Materials (2023)

Pulp exposure often leads to pulp necrosis, root fractures, and ultimate tooth loss. The repair of the exposure site with pulp capping treatment is of great significance to preserving pulp vitality, but its efficacy is impaired by the low bioactivity of capping materials and cell injuries from the local accumulation of oxidative stress. This study develops a Wnt3a-loaded hydroxyapatite nanowire@mesoporous silica (Wnt3a-HANW@MpSi) core-shell nanocomposite for pulp capping treatments. The ultralong and highly flexible hydroxyapatite nanowires provide the framework for the composites, and the mesoporous silica shell endows the composite with the capacity of efficiently loading/releasing Wnt3a and Si ions. Under in vitro investigation, Wnt3a-HANW@MpSi not only promotes the oxidative stress resistance of dental pulp stem cells (DPSCs), enhances their migration and odontogenic differentiation, but also exhibits superior properties of angiogenesis in vitro. Revealed by the transcriptome analysis, the underlying mechanisms of odontogenic enhancement by Wnt3a-HANW@MpSi are closely related to multiple biological processes and signaling pathways toward pulp/dentin regeneration. Furthermore, an animal model of subcutaneous transplantation demonstrates the significant reinforcement of the formation of dentin-pulp complex-like tissues and blood vessels by Wnt3a-HANW@MpSi in vivo. These results indicate the promising potential of Wnt3a-HANW@MpSi in treatments of dental pulp exposure.
Combination Therapy of Lox Inhibitor and Stimuli‐Responsive Drug for Mechanochemically Synergistic Breast Cancer Treatment
Authors: Shanshan Zhu, Tian Zhang, Huan Gao, Guorui Jin, Jin Yang, Xiaocong He, Hui Guo, Feng Xu
Journal: Advanced Healthcare Materials (2023)

Chemotherapy based on small molecule drugs, hormones, cycline kinase inhibitors, and monoclonal antibodies has been widely used for breast cancer treatment in the clinic but with limited efficacy, due to the poor specificity and tumor microenvironment (TME)-caused diffusion barrier. Although monotherapies targeting biochemical cues or physical cues in the TME have been developed, none of them can cope with the complex TME, while mechanochemical combination therapy remains largely to be explored. Herein, a combination therapy strategy based on an extracellular matrix (ECM) modulator and TME-responsive drug for the first attempt of mechanochemically synergistic treatment of breast cancer is developed. Specifically, based on overexpressed NAD(P)H quinone oxidoreductase 1 (NQO1) in breast cancer, a TME-responsive drug (NQO1-SN38) is designed and it is combined with the inhibitor (i.e., β-Aminopropionitrile, BAPN) for Lysyl oxidases (Lox) that contributes to the tumor stiffness, for mechanochemical therapy. It is demonstrated that NQO1 can trigger the degradation of NQO1-SN38 and release SN38, showing nearly twice tumor inhibition efficiency compared with SN38 treatment in vitro. Lox inhibition with BAPN significantly reduces collagen deposition and enhances drug penetration in tumor heterospheroids in vitro. It is further demonstrated that the mechanochemical therapy showed outstanding therapeutic efficacy in vivo, providing a promising approach for breast cancer therapy.
Cloning a profibrotic stem cell variant in idiopathic pulmonary fibrosis
Authors: Shan Wang, Wei Rao, Ashley Hoffman, Jennifer Lin, Justin Li, Tao Lin, Audrey-Ann Liew, Matthew Vincent, Tinne C. J. Mertens, Harry Karmouty-Quintana, Christopher P. Crum, Mark L. Metersky, David A. Schwartz, Peter J. A. Davies, Clifford Stephan, Soma S. K. Jyothula, Ajay Sheshadri, Erik Eddie Suarez, Howard J. Huang, John F. Engelhardt, Burton F. Dickey, Kalpaj R. Parekh, Frank D. McKeon, Wa Xian
Journal: Science Translational Medicine (2023)

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and rapidly fatal interstitial lung disease marked by the replacement of lung alveoli with dense fibrotic matrices. Although the mechanisms initiating IPF remain unclear, rare and common alleles of genes expressed in lung epithelia, combined with aging, contribute to the risk for this condition. Consistently, single-cell RNA sequencing (scRNA-seq) studies have identified lung basal cell heterogeneity in IPF that might be pathogenic. We used single-cell cloning technologies to generate "libraries" of basal stem cells from the distal lungs of 16 patients with IPF and 10 controls. We identified a major stem cell variant that was distinguished from normal stem cells by its ability to transform normal lung fibroblasts into pathogenic myofibroblasts in vitro and to activate and recruit myofibroblasts in clonal xenografts. This profibrotic stem cell variant, which was shown to preexist in low quantities in normal and even fetal lungs, expressed a broad network of genes implicated in organ fibrosis and showed overlap in gene expression with abnormal epithelial signatures identified in previously published scRNA-seq studies of IPF. Drug screens highlighted specific vulnerabilities of this profibrotic variant to inhibitors of epidermal growth factor and mammalian target of rapamycin signaling as prospective therapeutic targets. This profibrotic stem cell variant in IPF was distinct from recently identified profibrotic stem cell variants in chronic obstructive pulmonary disease and may extend the notion that inappropriate accrual of minor and preexisting stem cell variants contributes to chronic lung conditions.
On-skin biosensors for noninvasive monitoring of postoperative free flaps and replanted digits
Authors: Hao Wu, Zhuo Li, Zhao Xu, Xin Huang, Wei Guo, Jun Zhao, Jinwen Zhang, Shaoyu Liu, Miao Tang, Yuqi Qiu, Ganguang Yang, Juntong Zhu, Lili Liu, Yingjie Wu, Wei Lei, Pan Zhou, Zhouping Yin, Zhenbing Chen, Yutian Liu
Journal: Science Translational Medicine (2023)

Severe soft tissue defects and amputated digits are clinically common injuries. Primary treatments include surgical free flap transfer and digit replantation, but these can fail because of vascular compromise. Postoperative monitoring is therefore crucial for timely detection of vessel obstruction and survival of replanted digits and free flaps. However, current postoperative clinical monitoring methods are labor intensive and highly dependent on the experience of nurses and surgeons. Here, we developed on-skin biosensors for noninvasive and wireless postoperative monitoring based on pulse oximetry. The on-skin biosensor was made of polydimethylsiloxane with gradient cross-linking to create a self-adhesive and mechanically robust substrate that interfaces with skin. The substrate was shown to exhibit appropriate adhesion on one side for both high-fidelity measurements of the sensor and low risk of peeling injury to delicate tissues. The other side demonstrated mechanical integrity to facilitate flexible hybrid integration of the sensor. Validation studies using a model of vascular obstruction in rats demonstrated the effectiveness of the sensor in vivo. Clinical studies indicated that the on-skin biosensor was accurate and more responsive than current clinical monitoring methods in identifying microvascular conditions. Comparisons with existing monitoring techniques, including laser Doppler flowmetry and micro-lightguide spectrophotometry, further verified the sensor’s accuracy and ability to identify both arterial and venous insufficiency. These findings suggest that this on-skin biosensor may improve postoperative outcomes in free flap and replanted digit surgeries by providing sensitive and unbiased data directly from the surgical site that can be remotely monitored.
Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer
Authors: Aeson Chang, Edoardo Botteri, Ryan D. Gillis, Lukas Löfling, Caroline P. Le, Alexandra I. Ziegler, Ni-Chun Chung, Matthew C. Rowe, Stewart A. Fabb, Brigham J. Hartley, Cameron J. Nowell, Sasagu Kurozumi, Sara Gandini, Elisabetta Munzone, Emilia Montagna, Nina Eikelis, Sarah E. Phillips, Chikako Honda, Kei Masuda, Ayaka Katayama, Tetsunari Oyama, Steve W. Cole, Gavin W. Lambert, Adam K. Walker, Erica K. Sloan
Journal: Science Translational Medicine (2023)

Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated β 2 -adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or β 2 -adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting β 2 -adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive β 2 -adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.
No-Implant Interatrial Shunt for HFpEF
Authors: James E. Udelson, Colin M. Barker, Gerard Wilkins, Benjamin Wilkins, Robert Gooley, Siobhan Lockwood, Brian J. Potter, Christopher U. Meduri, Peter S. Fail, Darrell J. Solet, Kari Feldt, Jacob M. Kriegel, Tamaz Shaburishvili
Journal: JACC Heart Failure (2023)
Polypharmacy and Optimization of Guideline-Directed Medical Therapy in Heart Failure
Authors: Muhammad Shahzeb Khan, Sumitabh Singh, Matthew W. Segar, Muhammad Shariq Usman, Neil Keshvani, Andrew P. Ambrosy, Mona Fiuzat, Harriette G.C. Van Spall, Gregg C. Fonarow, Faiez Zannad, G. Michael Felker, James L. Januzzi, Christopher O’Connor, Javed Butler, Ambarish Pandey
Journal: JACC Heart Failure (2023)
Heart Failure Phenotypes According to Natriuretic Peptide Trajectory Following Initiation of Sacubitril/Valsartan
Authors: Reza Mohebi, Yuxi Liu, Peder L. Myhre, G. Michael Felker, Margaret F. Prescott, Ileana L. Piña, Javed Butler, Jonathan H. Ward, Scott D. Solomon, James L. Januzzi
Journal: JACC Heart Failure (2023)
Microbially Produced Imidazole Propionate Is Associated With Heart Failure and Mortality
Authors: Antonio Molinaro, Ina Nemet, Pierre Bel Lassen, Rima Chakaroun, Trine Nielsen, Judith Aron-Wisnewsky, Per-Olof Bergh, Lin Li, Marcus Henricsson, Lars Køber, Richard Isnard, Gerard Helft, Michael Stumvoll, Oluf Pedersen, J. Gustav Smith, W.H. Wilson Tang, Karine Clément, Stanley L. Hazen, Fredrik Bäckhed, Renato Alves, Chloe Amouyal, Ehm Astrid Andersson Galijatovic, Fabrizio Andreelli, Olivier Barthelemy, Jean-Philippe Bastard, Jean-Paul Batisse, Magalie Berland, Randa Bittar, Matthias Blüher, Peer Bork, Olivier Bourron, Mickael Camus, Dominique Cassuto, Cecile Ciangura, Luis Pedro Coelho, Jean-Philippe Collet, Marc-Emmanuel Dumas, S. Dusko Ehrlich, Line Engelbrechtsen, Leopold Fezeu, Sofia Forslund, Sebastien Fromentin, Pilar Galan, Philippe Giral, Jens Peter Gøtze, Torben Hansen, Tue H. Hansen, Agnes Hartemann, Bolette Hartmann, Serge Hercberg, Bridget Holmes, Jens Juul Holst, Malene Hornbak, Lesley Hoyles, Jean-Sebastien Hulot, Sophie Jaqueminet, Mathieu Kerneis, Jean Khemis, Ruby Kozlowski, Helle Krogh Pedersen, Michael Kuhn, Louise Mannerås-Holm, Lajos Marko, Laura Martinez-Gili Robin Massey, Nicolas Maziers, Jonathan Medina-Stamminger, Lucas Moitinho-Silva, Gilles Montalescot, Sandrine Moutel, Ana Luisa Neves, Michael Olanipekun, Jean-Michel Oppert, Christine Poitou, Francoise Pousset, Laurence Pouzoulet, Christine Rouault, Johanne Silvain, Henrik Vestergaard
Journal: JACC Heart Failure (2023)

Over the past years, it has become clear that the microbial ecosystem in the gut has a profound capacity to interact with the host through the production of a wide range of bioactive metabolites. The microbially produced metabolite imidazole propionate (ImP) is clinically and mechanistically linked with insulin resistance and type 2 diabetes, but it is unclear how ImP is associated with heart failure. The authors aimed to explore whether ImP is associated with heart failure and mortality. ImP serum measurements in 2 large and independent clinical cohorts of patients (European [n = 1,985] and North American [n = 2,155]) with a range of severity of cardiovascular disease including heart failure. Univariate and multivariate Cox regression analyses were performed to delineate the impact of ImP on 5-year mortality in the North American cohort, independent of other covariates. ImP is independently associated with reduced ejection fraction and heart failure in both cohorts, even after adjusting for traditional risk factors. Elevated ImP was a significant independent predictor of 5-year mortality (for the highest quartile, adjusted HR: 1.85 [95% CI: 1.20-2.88]; P < 0.01). The gut microbial metabolite ImP is increased in individuals with heart failure and is a predictor of overall survival.
Shedding Light on Latent Pulmonary Vascular Disease in Heart Failure With Preserved Ejection Fraction
Authors: Sergio Caravita, Claudia Baratto, Aurora Filippo, Davide Soranna, Céline Dewachter, Antonella Zambon, Giovanni Battista Perego, Denisa Muraru, Michele Senni, Luigi P. Badano, Gianfranco Parati, Jean-Luc Vachiéry, Marat Fudim
Journal: JACC Heart Failure (2023)

Among patients with heart failure with preserved ejection fraction (HFpEF), a distinct hemodynamic phenotype has been recently described, ie, latent pulmonary vascular disease (HFpEF-latentPVD), defined by exercise pulmonary vascular resistance (PVR) >1.74 WU.This study aims to explore the pathophysiological significance of HFpEF-latentPVD.The authors analyzed a cohort of patients who had undergone supine exercise right heart catheterization with cardiac output (CO) measured by direct Fick method, between 2016 and 2021. HFpEF-latentPVD patients were compared with HFpEF control patients.Out of 86 HFpEF patients, 21% qualified as having HFpEF-latentPVD, 78% of whom had PVR >2 WU at rest. Patients with HFpEF-latentPVD were older, with a higher pretest probability of HFpEF, and more frequently experienced atrial fibrillation and at least moderate tricuspid regurgitation (P < 0.05). PVR trajectories differed between HFpEF-latentPVD patients and HFpEF control patients (Pinteraction = 0.008), slightly increasing in the former and reducing in the latter. HFpEF-latentPVD patients displayed more frequent hemodynamically significant tricuspid regurgitation during exercise (P = 0.002) and had more impaired CO and stroke volume reserve (P < 0.05). Exercise PVR was correlated with mixed venous O2 tension (R2 = 0.33) and stroke volume (R2 = 0.31) in HFpEF-latentPVD patients. The HFpEF-latentPVD patients had had higher dead space ventilation during exercise and higher PaCO2 (P < 0.05), which correlated with resting PVR (R2 = 0.21). Event-free survival was reduced in HFpEF-latentPVD patients (P < 0.05).The results suggest that when CO is measured by direct Fick, few HFpEF patients have isolated latent PVD (ie, normal PVR at rest, becoming abnormal during exercise). HFpEF-latentPVD patients present with CO limitation to exercise, associated with dynamic tricuspid regurgitation, altered ventilatory control, and pulmonary vascular hyperreactivity, portending a poor prognosis.
Household Air Pollution and Adult Lung Function Change, Respiratory Disease, and Mortality across Eleven Low- and Middle-Income Countries from the PURE Study
Authors: Ying Wang, MyLinh Duong, Michael Brauer, Sumathy Rangarajan, Antonio Dans, Fernando Lanas, Patricio Lopez-Jaramillo, Thandi Puoane, Karen Yeates, Jephat Chifamba, Rita Yusuf, Zhiguang Liu, Yang Li, Lap Ah Tse, Deepa Mohan, Rajeev Gupta, Sanjeev Nair, PVM Lakshmi, Romaina Iqbal, Taniya Anto, Salim Yusuf, Perry Hystad
Journal: Environmental Health Perspectives (2023)

Background: Globally, household air pollution (HAP) is a major environmental hazard that affects respiratory health. However, few studies have examined associations between HAP and lung function decline and respiratory disease and mortality. Methods: We used data from the Prospective Urban and Rural Epidemiology study and examined adults residing in 240 rural communities in 11 low- and middle-income countries where HAP from cooking with solid fuels is common. Spirometry was conducted for 28,574 individuals at baseline and 12,489 individuals during follow-up (mean of 8 y between spirometry measures). In cross-sectional analyses, we compared lung function measurements [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio] in those who used solid fuels for cooking in comparison with clean fuels. Using repeated measurements of lung function, we examined the percent change in lung function measures per year, comparing individuals by baseline fuel type and individuals who used solid fuels at baseline but switched to clean fuels during follow-up. We also examined associations with prospective health events (any respiratory diseases, respiratory disease hospitalizations, and all-cause mortality). Results: In adjusted cross-sectional models, use of solid fuel in comparison with clean fuels was associated with lower FEV1 of −17.5mL (95% CI: −32.7, −2.3) and FVC of −14.4mL (95% CI: −32.0, 3.2), but not FEV1/FVC. In longitudinal analyses, individuals who switched from solid fuels to clean cooking fuels during follow-up (n=3,901, 46% of those using solid fuel at baseline), showed no differences in the annual rate of change in FEV1 or FVC, but had small improvements in FEV1/FVC change (0.2% per year, 95% CI: 0.03, 0.3). Individuals who switched from solid to clean fuels had a decreased hazard ratio for respiratory events of 0.76 (95% CI: 0.57, 1.00) in comparison with persistent solid fuel users, which was not attenuated by lung function measures. Conclusion: We observed modest associations between HAP exposure and lung function, lung function change, and respiratory disease and mortality. https://doi.org/10.1289/EHP11179